The present invention relates to a resin having a vinyl ether linker and more particularly, to a resin having a vinyl ether linker expressed by the following formula (1), useful for the synthesis of compounds having hetero atoms such as alcohol, thiol, imidazole, triazole and tetrazole by employing combinatorial chemical synthesis on solid supports, 
wherein {circle around (P)} is polystyrene-divinyl benzene; and n is an integer of 1 to 5.
Combinatorial chemical synthesis (CCS) is one of the important new methodologies to produce a diverse family of compounds simultaneously in the development of new compounds and new materials, while traditional chemical synthesis relied on one product from one reaction. CCS has become a powerful tool for rapidly discovering new lead compounds and optimizing molecular structures and properties thereof. Within the past several years, a number of reports have appeared that combinatorial chemistry using solid-phase chemical synthesis provides great potential, because solid-phase chemistry have several big advantages to develop combinatorial techniques such as possible to make a lot of libraries in one pot, simple to purify, simple to simultaneous multi step reaction, and possible to automation of reaction process, thus applicable for High Throughput Screening (HTS).
As explained above, CCS overcomes the uneconomicity and ineffectiveness of the conventional synthetic technologies but nevertheless it was seldom applied in the organic synthesis due to decreases in reaction rate and reactivity with using of solid support.
Linker moiety attaching between the compound and the solid-phase support has been introduced in order to solve such problems of decreases in reaction rate and reactivity in the performing CCS on the solid support. Large numbers of linkers have been developed and applied in the solid-phase support synthesis. Among those, 3,4-dihydro-2H-pyran-2-yl-methanol (DHP) linker is preferred as both linker and protecting group because it is facilitated for introduction and cleavage of alcohol, thiol, imidazole, triazole or tetrazole group. However, DHP linker is expensive and thus, it is difficult to apply for industrial manufacturing process.
Introduction of vinyl ether linker, which is facilitated to attach and detach pharmacologically active compounds such as alcohol, thiol, imidazole, triazole, or tetrazoleis, to Merrifield resin, which is a solid support, provides excellent utility value in the organic synthesis on solid-phase support.
Accordingly, an object of the present invention is to provide a resin having vinyl ether liker which is also a protecting group.
In accordance with one aspect of the present invention, there is provided a method for preparing a resin having vinyl ether liker. Another object of the present invention is to provide a process for preparing hetero atom-containing compounds such as alcohols, thiols, triazoles and tetrazoles by employing the resin having vinyl ether linker of the present invention as a solid-phase support in Combinatorial chemistry synthesis.
The present invention provides a resin having vinyl ether linker of formula (1) which is useful for combinatorial chemical synthesis, 
wherein {circle around (P)} is polystyrene-divinyl benzene; and n is an integer of 1 to 5.
The present invention is described in more detail as set forth hereunder. The resin having vinyl ether linker of the present invention is prepared as the following 3-steps comprising:
(1) a reduction of methyl (4-hydroxybenzyl)ester of formula (2) to 4-hydroxylphenethyl alcohol of formula (3), 
wherein the reduction is performed by adding excess amount of a typical reducing agent, preferably 2.0 equivalent of lithium aluminum hydride or diisopropylaluminum hydride at 0xc2x0 C. and then stirring at room temperature in a typical aprotic organic solvent such as tetrahydrofuran;
(2) a reaction of the obtained compound of formula (3) with ethylvinyl ether of formula (4) to produce 4-(2-vinyloxyethyl)phenol of formula (5), 
wherein the phenethyl alcohol of formula (3) is reacted with ethylvinyl ether of formula (4) in the presence of mercury catalyst at room temperature; and
(3) a reaction of the obtained compound of formula (5) with Merrifield resin of formula (6) to produce the desired product resin having vinyl ether linker of formula (1), 
wherein the reaction is performed in the presence of a base catalyst such as sodium alkoxide and sodium hydride in a typical polar solvent such as dimethylacetamide at 50xc2x0 C. and after the reaction was performed, no residual Merrifield resin was detected, which was identified by the nonexistence of peak corresponding to chlorine atom (Cl) in the X-ray photoelectron spectroscopy (XPS) element analysis.
More detailed reaction condition and the relative elemental analysis results are given in Example 1.
The present invention further provides an application of the resin having vinyl ether linker of formula (1) as a solid-phase support to CCS. A preferred example is a preparation of hetero atom-containing compounds of formula (7),
HYxe2x80x94(CH2)mxe2x80x94Xxe2x80x83xe2x80x83(7)
wherein Y is O or N;
X is H, OH, SH, a halogen atom, phenyl, phenyl or biphenyl substituted with halogen atom(s), or 
formed by bonding another hetero atom (Xxe2x80x2) with Y, where Y and Xxe2x80x2 are independently hetero atom(s), of which number is 1 to 5, and bonded C1-C4 alkylene or alkenyl; and
M is an integer of 1 to 4.
The following scheme 1 shows a process of introducing the hetero atom-containing compound of formula (7) to the resin having vinyl ether linker of formula (1) on a solid-phase support and a process for cleaving the same from the solid-phase support, 
wherein {circle around (P)}, X, Y, n and m are previously defined.
In Scheme 1, the introduction of the hetero atom-containing compound of formula (7) to the resin having vinyl ether linker of formula (1) on a solid-phase support is performed in the presence of an acid catalyst chosen from camphorsulfonic acid, trifluoroacetic acid and pyridinium xcfx81-toluenesulfonate in 1,2-dichloroethane. Particularly, when the compound of formula (7) contains O or S, it is preferred to perform the reaction in the presence of pyridinium xcfx81-toluenesulfonate and when the compound of formula (7) contains N, it is preferred to perform the reaction in the presence of camphorsulfonic acid or trifluoroacetic acid. The compound of formula (7) is preferably used in the range of from 3 to 5 equivalents based to the compound of formula (1) and the formation of the compound (8) is indirectly identified by detecting disappearance of olefin peak, which is shown in the compound of formula (1), in IR spectrum.
After performing various organic reactions on solid-phase support, the cleavage reaction of the hetero atom-containing compound from the solid support is carried in the presence of excess amount of an acid and solvent, preferably HCl/methanol, at room temperature. The production of the hetero atom-containing compound is identified by IR, NMR, and Mass spectrographic analyses. More detailed reaction conditions for introduction and cleavage of the hetero atom-containing compound of formula (7) to/from the resin having vinyl ether linker of formula (1) on a solid-phase support and the relative elemental analysis results are given in Examples 2 and 3.
As described above, the resin having vinyl ether linker is a novel solid support useful for organic syntheses due to simple introduction and cleavage of compounds containing alcohol, thiol, imidazole, triazole, or tetrazole.
The following examples are intended to further illustrate the present invention without limiting its scope.